title: A functional polymorphism in the promoter of ERK5 gene interacts with tobacco smoking to increase the risk of lung cancer in Chinese populations.
abstract: Mitogen/extracellular signal-regulated kinase-5 (MEK5)/extracellular signal-regulated protein kinase-5 (ERK5) pathway plays a pro-oncogenic role in tumourigenesis by anticell apoptosis, promoting cell proliferation and differentiation in response to extracellular stimuli. As overexpressed MEK5/ERK5 is involved in the development of lung cancer, we hypothesised that the single nucleotide polymorphisms (SNPs) in MEK5 and ERK5 genes may influence gene expression and thus be associated with lung cancer risk. Five putative functional polymorphisms (rs3743353T>C, rs7172582C>T and rs2278076A>G of MEK5 and rs3866958G>T and rs2233083C>T of ERK5) were genotyped in two independent case-control studies with a total of 1559 lung cancer patients and 1679 controls in southern and eastern Chinese population. We found the rs3866958G>T of ERK5 was significantly associated with lung cancer risk, while other SNPs were not. Compared with the rs3866958TG/TT genotypes, the GG genotype conferred an increased risk of lung cancer (odds ratio = 1.30, 95% confidence interval = 1.12-1.51, P = 5.0×10(-4)), and this effect was more pronounced in smokers, accompanying with a significant interaction with smoking (P interaction = 0.013). The GG genotype also had significant higher mRNA levels of ERK5 in lung cancer tissues than TG/TT genotypes (P = 1.0×10(-4)); the luciferase reporter with the G allele showed significant higher transcription activities than the T allele, especially after the treatment with tobacco extract in vitro. Our data indicated that the functional polymorphism rs3866958G>T in ERK5 was associated with an increased lung cancer risk in smokers by virtue of the positive interaction with smoking on promoting the ERK5 expression, which might be a valuable indicator for predicting lung cancer risk in smokers.
authors.affiliation: The Institute for Chemical Carcinogenesis, The State Key Lab of Respiratory Disease, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, People's Republic of China.
authors.forename: Fuman
authors.initials: F
authors.lastname: Qiu
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Wenxiang
authors.initials: W
authors.lastname: Fang
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Li
authors.forename: Rongrong
authors.initials: R
authors.lastname: Yang
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Yang
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Deng
authors.forename: Binfang
authors.initials: B
authors.lastname: Huang
authors.forename: Chenli
authors.initials: C
authors.lastname: Xie
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jiachun
authors.initials: J
authors.lastname: Lu
mesh_terms: D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D048671:MAP Kinase Kinase 5 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics*; D010936:Plant Extracts / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics
chemical_list: D010936:Plant Extracts; D008156:Luciferases; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human